The present invention relates to novel compounds and processes useful in the synthesis of certain prostaglandin analogs. Specifically, the invention relates to intermediates and processes useful in the synthesis of certain 11-oxa prostaglandins.
Substituted tetrahydrofuran analogs of D and F series prostaglandins for use in treating glaucoma and ocular hypertension are disclosed in commonly assigned U.S. Pat. No. 5,994,397, the entire contents of which are by this reference incorporated herein. 11-oxa PGF2xcex1 analogs and/or synthetic schemes for their preparation are disclosed in Hanessian, et al., Carbohydrate Research, 141:221-238 (1985); Thiem et al., Liebigs Ann. Chem., 2151-2164 (1985); Arndt, et al., S. African J. Chem. 34:121-127 (1981); and U.S. Pat. No. 4,133,817. The entire contents of these references are hereby incorporated herein.
Previous routes to 11-oxa prostaglandins employ a C1-C2 olefination reaction of a tetrahydrofuran-2-carboxaldehyde for the introduction of the xcfx89-chain. The xcex1-chain may be introduced before or after this step. The tetrahydrofuran-2-carboxaldehyde may be prepared from several readily available carbohydrates, which provide the four carbons of the tetrahydrofuran core and C1 of the xcfx89-chain. The following carbohydrates have been used as starting materials in this approach: D-sorbitol (J. Thiem and H. Lxc3xcders, Liebigs Ann. Chem., 2151 (1985) and S. Hanessian, Y. Guindon, P. Lavallxc3xa9e and P. Dextraze, Carbohydrate Research, 141, 221 (1985)), D-xylose and D-glucose (G. J. Lourens and J. M. Koekemoer, Tetrahedron Letters, 43:3719 (1975) and R. R. Arndt, J. M. Koekemoer, G. J. Lourens and E. M. Venter, S.-Afri. Tydskr. Chem., 34:121 (1981)).
It is desirable, especially to improve therapeutic effect, to isolate the active isomer of the desired compound. In order for development of a pharmaceutical product comprising the enantiomerically enriched compound to be feasible, an economically viable synthetic route that will yield commercial quantities of the material is required.
Previously known syntheses of 11-oxa prostaglandins have suffered from various drawbacks that limit their usefulness for production of commercial quantities of the desired material. Such drawbacks include, without limitation, low yields, costly, time consuming, or inefficient synthetic sequences, and/or difficult or inadequate separation of the undesired enantiomer or epimer. A need exists, therefore, for an improved, commercially viable synthetic approach for 11-oxa prostaglandin analogs.
The present invention is directed to novel processes and intermediates useful in the preparation of preferred enantiomers of certain 11-oxa prostaglandins. The processes and intermediates of the present invention are particularly useful in the preparation of [2R(1E,3R),3S(4Z),4R]-7-[Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl]-4-heptenoic acid and its C1 esters.
The present invention is directed to improved processes and intermediates for the preparation of certain 11-oxa prostaglandin analogs, including salt, ester, ether, alcohol, amine and amide derivatives thereof, and especially the 11-oxa prostaglandin analogs of formula I: 
wherein:
R is H or a pharmaceutically acceptable cationic salt moiety, or CO2R forms a pharmaceutically acceptable ester moiety;
R9O and R15O are the same or different and constitute a free or functionally modified hydroxy group;
--- is a single or trans double bond;
X=(CH2)q or (CH2)qO; q=1-6; and
Y=a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, or a free or functionally modified hydroxy or amino group;
or Xxe2x80x94Y=(CH2)mY1, m=0-6, 
xe2x80x83wherein:
W=CH2, O, S(O)m, NR10, CH2CH2, CHxe2x95x90CH, CH2O, CH2S(O)m, CHxe2x95x90N, or CH2NR10;
m=0-2;
R10=H, alkyl, acyl;
Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, OH; and
----=single or double bond.
The inventive processes and intermediates are preferably used to prepare the 11-oxa prostaglandin analogs of formula II: 
wherein:
R=H or alkyl;
X=CH2CH2 or CH2O; and
Y=phenyl, optionally substituted with halo or trihalomethyl.
The most preferred product of the presently claimed processes is isopropyl [2R(1E,3R),3S(4Z),4R]-7-[Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl]-4-heptenoate as provided by formula II, wherein R=isopropyl, X=CH2O, and Y=3-chlorophenyl.
It has now been discovered that by utilizing novel intermediates and by making certain modifications and additions to known synthetic processes, yields and purity of intermediates and ultimately the desired end product are significantly improved. The improved processes of the present invention thus provide a commercially viable route for the preparation of therapeutically useful 11-oxa prostaglandin analogs.
The novel process comprises conversion of D-sorbitol (1) to anhydro-D-glucitol (2) using acid and heat. Treatment of 2 with a trialkyl orthoalkanoate (preferred is trimethyl orthoacetate) affords ortho ester III (R3 is alkyl or cycloalkyl, preferred is R3=CH3), which is silylated on the free hydroxy group using a silyl halide or triflate R4R5R6SiX (R4, R5, R6=same or different=alkyl, cycloalkyl, or aryl, preferred is R4 and R5=Ph and R6=tert-butyl; X=Cl, Br, I, or OSO2CF3, preferred is X=Cl or OSO2CF3) in the presence of an amine base (e.g., NEt3 or imidazole) to give silyl ether IV (R4, R5, R6=same or different=alkyl, cycloalkyl, or aryl, preferred is R4 and R5=Ph and R6=tert-butyl). 
Treatment of IV with acid and a hydroxylic solvent provides triol V, which is treated with dimethoxypropane in the presence of catalytic acid to yield acetonide VI. Oxidation of VI with, for example, DMSO/carbodiimide/acid affords ketone VII, which is condensed with Ph3P=CHCO2R7 (R7=alkyl, aryl, or cycloalkyl; R7=alkyl is preferred) to give enoate VIII (R7=alkyl, aryl, or cycloalkyl, R7=alkyl is preferred). 
Unsaturated ester VIII is reduced with hydrogen gas over a metal catalyst (e.g., Pd/C) to provide saturated ester IX, which is reduced with a metal hydride reagent (e.g., lithium aluminum hydride or lithium borohydride; preferred is lithium aluminum hydride) to give alcohol X. Treatment of alcohol X with R8SO2X (R8=alkyl, aryl, or trifluoromethyl, preferred is methyl, 4-methylphenyl, or trifluoromethyl; X=halide, preferably chloride, or OSO2R8 (i.e., R8SO2X forms an anhydride)) in the presence of an amine base (such as pyridine, triethylamine, or DBU) yields sulfonate XI, which is reacted with a metal cyanide (preferably NaCN) in DMSO to afford nitrile XII. Oxidative deprotection of XII with H5IO6 gives aldehyde XIII, which is condensed with (MeO)2P(O)CH2C(O)xe2x80x94Xxe2x80x94Y (X and Y are as defined for formula I; preferred is X=O and Y=3-chlorophenyl) in the presence of an amine base (preferred are triethylamine and DBU) and LiCl or LiBr to provide trans-enone XIV. Alternatively, aldehyde XIII can be condensed with Ph3Pxe2x95x90CHC(O)xe2x80x94Xxe2x80x94Y (X and Y are as defined for formula I) to afford XIV. 
Reduction of enone XIV to the corresponding allylic alcohol can be performed under several conditions. Reduction using NaBH4/CeCl3 affords the alcohol XV as a nearly 1:1 mixture of diastereomers. More efficient production of the 15xcex1 diastereomer can be achieved by using stoichiometric (xe2x88x92)-B-chlorodiisopinocampheylborane, or catalytic (3aR)-Tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]oxazaborole [(R)-2-methyl-CBS-oxazaborolidine, which is commercially available from Aldrich Chemical Co., Milwaukee, Wis.] with stoichiometric BH3 as the reducing agent. Similarly, use of stoichiometric (+)-B-chlorodiisopinocampheylborane, or catalytic (3aS)-Tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]oxazaborole [(S)-2-methyl-CBS-oxazaborolidine, which is commercially available from Aldrich Chemical Co., Milwaukee, Wis.] with stoichiometric BH3 affords the 15xcex2 diastereomer predominantly. Optionally, desilylation of XV using tetra-n-butylammonium fluoride affords diol XVI, for which the normal phase silica gel 20 chromatographic separation of the two carbon 15 epimers is most efficiently achieved. Protection of XV or XVI using a silyl halide or triflate R4R5R6SiX (R4, R5, R6=same or different=alkyl, cycloalkyl, or aryl, preferred is R4 and R5=Ph and R6=tert-butyl; X=Cl, Br, I, or OSO2CF3, preferred is X=Cl or OSO2CF3) in the presence of an amine base (e.g., NEt3 or imidazole) provides XVII. 
Nitrile XVII is treated with diisobutylaluminum hydride below xe2x88x9220xc2x0 C. followed by addition of aqueous acid to give aldehyde XVIII. Wittig condensation of XVIII with Ph3P+(CH2)3CO2R Brxe2x88x92(R=H, alkyl, aryl, cycloalkyl, etc.; preferred is alkyl) in a suitable solvent (preferred are toluene and THF and mixtures thereof) in the presence of a strong base [e.g., MN(SiMe3)2 (M=Na, Li, or K), KOBut, or n-butyllithium, preferred is NaN(SiMe3)2] in the temperature range xe2x88x9278xc2x0 C. to 25xc2x0 C. (preferred is the range xe2x88x9240xc2x0 C. to 0xc2x0 C.) affords XIX, which is deprotected using tetra-n-butylammonium fluoride to yield a compound of formula I where R9=R15=H. One skilled in the art will appreciate that production of such compound with R9 and R15 equal to groups other than H is possible by introduction of said groups at the appropriate time; for example, reaction of alcohol XV with CH3OSO2CF3 in CH2Cl2 in the presence of 2,6-di-t-butylpyridine, followed by the rest of the reaction sequence, would afford I with R9=H and R15=CH3. 
The term xe2x80x9cacylxe2x80x9d represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and single bond to another carbon atom.
The term xe2x80x9cacylaminoxe2x80x9d represents a group that is linked by an amino atom that is connected to a carbon atom that has a double bond to an oxygen group and a single bond to a carbon atom or hydrogen atom.
The term xe2x80x9cacyloxyxe2x80x9d represents a group that is linked by an oxygen atom that is connected to a carbon atom that has a double bond to an oxygen atom and single bond to another carbon atom.
The term xe2x80x9calkenylxe2x80x9d includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon double bond. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkenyl groups include, allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.
The term xe2x80x9calkoxyxe2x80x9d represents an alkyl group attached through an oxygen linkage.
The term xe2x80x9calkylxe2x80x9d includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. The alkyl groups may be substituted with other groups, such as halogen, hydroxyl or alkoxy. Preferred straight or branched chain alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
The term xe2x80x9calkylaminoxe2x80x9d represents an alkyl group attached through a nitrogen linkage.
The term xe2x80x9carylxe2x80x9d refers to carbon-based rings which are aromatic. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted with other groups, such as lower alkyl, or halogen.
The term xe2x80x9ccationic salt moietyxe2x80x9d includes alkali and alkaline earth metal salts as well as ammonium salts.
The term xe2x80x9ccycloalkylxe2x80x9d includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl or lower alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cylopentyl and cyclohexyl.
The term xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d represents fluoro, chloro, bromo, or iodo.
The term xe2x80x9clower alkylxe2x80x9d represents alkyl groups containing one to six carbons (C1-C6).
The term xe2x80x9cfree hydroxy groupxe2x80x9d means an OH. The term xe2x80x9cfunctionally modified hydroxy groupxe2x80x9d means an OH which has been functionalized to form: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for the hydrogen; an ester, in which an acyl group is substituted for the hydrogen; a carbamate, in which an aminocarbonyl group is substituted for the hydrogen; or a carbonate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, or alkynyloxy-carbonyl group is substituted for the hydrogen. Preferred moieties include OH, OCH2C(O)CH3,OCH2C(O)C2H5, OCH3, OCH2CH3, OC(O)CH3, and OC(O)C2H5.
The term xe2x80x9cfree amino groupxe2x80x9d means an NH2. The term xe2x80x9cfunctionally modified amino groupxe2x80x9d means an NH2 which has been functionalized to form: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, alkynyl-, or hydroxy-amino group, wherein the appropriate group is substituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-, cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-amino group, wherein the appropriate group is substituted for one or both of the hydrogens; an amide, in which an acyl group is substituted for one of the hydrogens; a carbamate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-carbonyl group is substituted for one of the hydrogens; or a urea, in which an aminocarbonyl group is substituted for one of the hydrogens. Combinations of these substitution patterns, for example an NH2 in which one of the hydrogens is replaced by an alkyl group and the other hydrogen is replaced by an alkoxycarbonyl group, also fall under the definition of a functionally modified amino group and are included within the scope of the present invention. Preferred moieties include NH2, NHCH3, NHC2H5, N(CH3)2, NHC(O)CH3, NHOH, and NH(OCH3).
For purposes of the foregoing and following definitions, the term xe2x80x9calkylxe2x80x9d or xe2x80x9cpharmaceutically acceptable ester moietyxe2x80x9d means any ester moiety that would be suitable for therapeutic administration to a patient by any conventional means without significant deleterious health consequences. Similarly, the term xe2x80x9cophthalmically acceptable ester moietyxe2x80x9d means any pharmaceutically acceptable ester moiety that would be suitable for ophthalmic application, i.e. non-toxic and non-irritating. Preferred are ophthalmically acceptable esters such as alkyl and alkylcycloalkyl esters of carboxylic acids. Most preferred are C2-C5 alkyl esters of carboxylic acids, and especially isopropyl esters.
In the foregoing illustrations, as well as those provided hereinafter, wavy line attachments indicate that the configuration may be either alpha (xcex1) or beta (xcex2). Dashed lines on bonds indicate a single or double bond. Two solid lines between carbons specify the configuration of the relevant double bond. Hatched lines indicate the xcex1 configuration. A solid triangular line indicates the xcex2 configuration.
In the following Examples, the following standard abbreviations are used: g=grams (kg=kilograms; mg=milligrams); mol=moles (mmol=millimoles); mL=milliliters; mm Hg=millimeters of mercury; mp=melting point; bp=boiling point; h=hours; and min=minutes. In addition, xe2x80x9cNMRxe2x80x9d refers to nuclear magnetic resonance spectroscopy and xe2x80x9cMSxe2x80x9d refers to mass spectrometry.